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Concise syntheses and HCV NS5B polymerase inhibition of (2'R)-3 and (2'S)-2'-ethynyluridine-10 and related nucleosides.

Authors
  • Bennett, Frank1
  • Buevich, Alexei V2
  • Huang, Hsueh-Cheng3
  • Girijavallabhan, Vinay4
  • Kerekes, Angela D4
  • Huang, Yuhua4
  • Malikzay, Asra5
  • Smith, Elizabeth5
  • Ferrari, Eric5
  • Senior, Mary6
  • Osterman, Rebecca6
  • Wang, Lingyan4
  • Wang, Jun4
  • Pu, Haiyan4
  • Truong, Quang T4
  • Tawa, Paul5
  • Bogen, Stephane L4
  • Davies, Ian W4
  • Weber, Ann E4
  • 1 Merck & Co., Inc., MRL., Department of Medicinal Chemistry, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. Electronic address: [email protected]
  • 2 Merck & Co., Inc., MRL., Department of Structure Elucidation, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. Electronic address: [email protected]
  • 3 Merck & Co., Inc., MRL., Department of Viirology, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. Electronic address: [email protected]
  • 4 Merck & Co., Inc., MRL., Department of Medicinal Chemistry, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • 5 Merck & Co., Inc., MRL., Department of Viirology, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • 6 Merck & Co., Inc., MRL., Department of Structure Elucidation, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Dec 01, 2017
Volume
27
Issue
23
Pages
5349–5352
Identifiers
DOI: 10.1016/j.bmcl.2017.06.064
PMID: 29056248
Source
Medline
Keywords
License
Unknown

Abstract

(2'R)-Ethynyl uridine 3, and its (2'S)-diastereomer 10, are synthesised in a divergent fashion from the inexpensive parent nucleoside. Both nucleoside analogues are obtained from a total of 5 simple synthetic steps and 3 trivial column chromatography purifications. To evaluate their effectiveness against HCV NS5B polymerase, the nucleosides were converted to their respective 5'-O-triphosphates. Subsequently, this lead to the discovery of the 2'-β-ethynyl 18 and -propynyl 20 nucleotides having significantly improved potency over Sofosbuvir triphosphate 24.

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